Electrostimulating system

ABSTRACT

An electrostimulating apparatus that generates a relaxing sequence suitable for stimulating the striated or vasoactive muscle fibre for the activation of the microcirculation, based on three fundamental parameters: the width of the electric stimulation: the frequency of said stimulation and the time intervals wherein a plurality of width/frequency combinations follows.

The invention refers to an electrostimulating system comprising meansfor producing an electric stimulation that consists of bioactiveneuromodulation of the neurovegetative system, of the striated-musclesystem, of the smooth muscle and of the mixed nervous structure,particularly suitable for producing inter alia phenomena of muscularcontraction and relaxation by means of emulation of the action of thenerve fibre that innerves a skeletal muscle or of the neuroceptors ofthe sympathetic system that interact with the smooth muscle of thevessels.

Equally, depending on the type of electric stimulation and on theconfiguration parameters, a consequent induced bioactive neuromodulationcan be generated that is suitable for producing vasoactive phenomena inthe microcirculaton and in the macrocirculation, which are in turnmediated by phenomena connected with the direct stimulation of thesmooth muscle and by essentially catecholamine energy phenomena by meansof stimulation of the postsynaptic receptors.

The system thus produces stimulation sequences that induce reproducibleand constant neurophysiological responses; in particular, but notrestricted thereto, the sequences of activation of the microcirculation(ATMC) and relaxation of the muscle fibre (DCTR) are able to stimulatedifferent functional contingents, including but not limited to thestriated muscle, the smooth muscle and the peripheral mixed nerve.

The stimulation sequences are assembled on three fundamental parameters:the width of the stimulus, the frequency of the stimulus and the timewherein different combinations of width/frequency follow each other. Thegeneral operating model reflects the digital-analogue transduction thatoccurs in nervous transmission.

WO 02/09809 discloses an apparatus for the treatment of muscular,tendinous and vascular pathologies by means of which a series ofelectric pulses lasting from 10 to 40 microsecs are applied to a patientand at variable intensity, depending on the impedance and conductance ofthe tissue subjected to stimulation, typically from 100 to 170microampere. These electric pulses are able to produce a relaxing,anti-inflammatory and vasoactive effect. Such levels of current and theconnected level of energy transferred, below 5 microjoules, cannotcreate polarisation or ionisation of metallic structures and aretherefore absolutely compatible with the presence in the stimulatedorganism of, for example, metal prostheses, or of intrauterine-coilcontraceptive devices and cardiostimulators or implanted defibrillators(pacemakers).

U.S. Pat. No. 5,725,563 discloses a method and a system of adrenergicstimulation of the sympathetic nervous system relative to thecirculation of the patient wherein electric pulses are generated andsimultaneously impedance of the cytoplasm contained in the space betweenthe stimulation electrodes is measured. In this case, the specificeffects of the disclosed system are cited, namely the vasoconstrictionthat is a consequence of activation of the alphaadrenergic postsynapticreceptors that modify the venous tone, thereby producingvasoconstriction and consequent vascular and lymphatic drainage. In thiscase, to obtain this specific effect, stimulations are proposed in arange of frequencies absolutely below 2 Hz and preferably of 1.75 Hzwith currents below 350 microAmperes and preferably below 250microAmperes with energy transfer around 10 microjoule. In particular,the pulses generated by the above-mentioned stimulator are subordinatedto the measurement of impedance so as to vary the width of the pulse infunction thereof.

However, this system produces only the effect of a “peristaltic pump”due to the periodical “vasoconstriction” and subsequent “long” period of“relaxation” and is obtained by means of the delivery of very lowfrequency pulses (<2 Hz) to the smooth muscles of the vessel. However,in addition to being limiting and requiring careful measuring ofimpedance, it produces limited effects and requires stimulations thatare extremely prolonged over time to obtain visible and effectiveeffects.

On the contrary, this invention also solves all the problems that besetthe prior art and significantly increases the disclosed positiveeffects, having a direct action on postsynaptic activity, it producesdirect effects on synapses or the motor plate of the skeletal muscleinvolved.

The invention provides a combination of: an electrostimulating apparatusfor applying electrical stimuli to biological tissues; heat exchangingmeans, arranged to exchange heat with said tissues.

Advantageously, the apparatus and the method provided by the inventionexploit the principle of achieving significant bioreaction variations.

The invention may be better understood with reference to the attacheddrawings that illustrate certain embodiments by way of non-limitingexample, wherein:

FIG. 1 shows a Cartesian graph of time/intensity of current, disclosingthe intensity and time thresholds;

FIG. 2 shows a graph illustrating a relaxing sequence, or DCTR sequence,according to the invention;

FIG. 3 shows a DCTR sequence plot, carried out on a healthy subject;

FIG. 4 shows a plot like the one in FIG. 3, but carried out on a furtherhealthy subject;

FIG. 5 shows three surface electromyograms, with stimulation frequenciesof 1, 15 and 30 Hertz;

FIG. 6 shows a graph illustrating a reactivation sequence of themicrocirculation, or ATMC sequence, according to the invention;

FIG. 7 shows a polygraph recorded during administration of an ATMCsequence to a healthy subject, in the presence of electric stimulation;

FIG. 8 shows a polygraph like the one in FIG. 7, but conducted in theabsence of electric stimulation;

FIG. 9 shows a graph highlighting the discontinuous variation of thebioreaction obtained during administration of an ATMC sequence;

FIG. 10 shows graphic histograms of flow plots recorded in the presenceand/or absence of ATMC sequences;

FIG. 11 shows flow variations recorded at the same time as theadministration of an ATMC sequence like the one illustrated in FIG. 7;

FIG. 12 shows flow variations similar to those in FIG. 11, but recordedduring the administration of an ATMC sequence like the one illustratedin FIG. 8;

FIG. 13 shows further flow variations like those in FIG. 12;

FIG. 14 illustrates a combination of an ATMC sequence with a thermalheating stimulus.

The nervous cell is responsible for the formation and transmission ofthe nervous pulses, which regulate the operation of the entire organism.This nervous cell is formed by a cell body or “soma” wherefrom brancheslead: the “dendrites” along which the pulse has a centripetal direction(i.e. towards the cell body) and the “axon”, along which the pulses aremediated by the soma to the periphery, i.e. in a centrifugal direction.The pulses that do not arise from the soma of the cell are transmittedto the latter by other nervous cells or by specialised structures(receptors) or originate directly with the fibres, as in the case offree nerve ends responsible for collecting painful stimuli.

The pulse can travel towards the centre or vice versa. In the first caseit is defined as being afferent and the result, analysed at the level ofthe Central Nervous System, is the acquisition of conscious information(sensitive stimulation) or unconscious information (e.g. automaticregulation of balance). The pulse that travels from the centre to theperiphery is therefore defined as efferent and is able to cause thestimulation of the innerved organ or tissue.

The result of this may be muscular contraction, a glandular secretion,variations in cell metabolism, vasodilatation, vasoconstriction, and soon. Transmission of the pulse between the nerve fibres and the cells ofa tissue occurs with the help of synapsis. The latter is terminaldilation (terminal button) of the axon that is in contact with themembrane of the cell to which the pulse is transmitted. A diminution ofmembrane potential in turn causes depolarisation that subsequentlyextends to the entire cell. The pulse that runs along the nerve fibre ismerely the propagation of a depolarisation wave called action potential.

The nervous pulse may arise directly from the cell, but more often itoriginates from the stimulation of one of its parts, stimulated forexample by pressure or a painful sensation.

The striated muscle fibre consists of thousands of myofibrils,consisting of two types of filamentous protein, that are arrayed in analternating manner: the bigger the myosin the thinner the actin. Theactin has light streaks defined as I bands, whereas with actin andmyosin dark streaks known as A bands are created. The complex formed byan A band and by two adjacent semibands I is given the name “sarcomere”.Between two adjacent sarcomeres there exists a contact zone and asarcoplasmic reticulum for the control of the contraction consisting oftwo different types of tubules: T tubules and longitudinal tubules.

Each muscle fibre receives pulses from the motor nerve fibre via theneuromuscular junction, which takes the name motor plate.

When the pulse arrives this causes depolarisation known as “platepotential” which generates action potential along the entire length ofthe muscle fibre, which causes it to contract. It is at this pointopportune to recall the definition of the “chronaxy” and “rheobasis”parameters regarding the excitability characteristics of the nerve andmuscle fibres. Chronaxy (Kr) is defined as the time (expressed in msec)required by a current intensity to reach a value that is twice therheobasis (muscle sensitivity). Rheobasis (Rh) is in turn defined as theminimum (liminal) measurable current intensity required to excite acell.

If the stimulating current is limited to a short time of the order ofmsec it will be observed that the shorter the width of the current is,the greater its intensity will have to be to reach the threshold. Asshown in FIG. 1, by plotting the intensity-time curve two intensity andtime thresholds are defined. The theoretical construction of the curveis achieved on the basis of the capacitive features of the axonmembranes. The higher excitability is, the more concave the curve willbe in relation to the axes because smaller products (i·t), i.e. smallerquantities of electricity will correspond to its points. When one wishesto determine the excitability of a nerve or muscle in vivo chronaxy isused. Chronaxy and rheobasis are in fact interconnected ascharacteristics of the nerve fibre. By means of “Lorenz stimulation withmodulated frequency and amplitude” the excitation of the nerve fibrescan be obtained by means of the summation effect of several subthresholdsignals that are not able to excite the fibre, which however, bycombining their effects together, are able at a certain point to excitethe fibre. The summation effect, with the same produced pulse amplitude,will depend on the amplitude of the signal and on the bioreaction thatis therefore connected to frequency, which in turn interact with therheobasis-chronaxy ratio.

To demonstrate this behaviour, an analytical study of the physiologicalresponses was conducted in combination with “Lorenz stimulation” byapplying two different experimental procedures.

A first procedure is based on the use of a relaxing action sequence orDCTR, whose frequency and width characteristics are set out in FIG. 2.

The aim of the reported experiment is to prove the validity of thehypothesis that such a sequence, disclosed in WO 02/09809 andappropriately designed to have a relaxing effect on the muscle fibres,has a prevailing action on the activity of the skeletal muscle.Stimulation was achieved by measuring with sophisticated digitalpolygraph laboratory instruments with the possibility of samplinghigh-speed and high-frequency signals. The latter were recorded at thelevel of the short adductor muscle of the thumb and palm of the hand.For the short adductor muscle of the thumb a pair of plate electrodes(Ag+Cl−) was used through preamplification of the analogue signal at5000 gains, passband 5 Hz-3 KHz. To the palm of the hand anelectro-resistant transducer was applied comprising two surfaceelectrodes, with 1:10 μohm preamplification.

The DCTR stimulation sequence was administered to two different healthysubjects. For each of them four polygraphs were recorded (as describedpreviously), for three identical DCTR sequence cycles run consecutively.Two of the above polygraphs, obtained from different subjects, wereillustrated in FIGS. 3 and 4. The stimulator electrodes were placed nearthe recording seats, along the route of the median nerve on the palmarsurface of the wrist.

In both plots, carried out on healthy subjects, the median nerve wasstimulated at the wrist with the DCTR sequence repeated three times,measuring on the short adductor muscle of the thumb of the thenareminence with a transducer of skin impedance.

Each polygraph contains three plots separated into: top, middle andbottom.

The top plot shows the muscle responses obviously after discounting thestimulation artefacts, which responses are expressed in frequencyhistograms, whilst in the intermediate plot the skin conductancevariations appear. In the bottom plot the stimulation sequence is shown,wherein the graphically “densest” part represents the rapid increasephases of the frequency.

As can be seen from the analysis of the DCTR sequence, the basicvariation is the variation in the frequency of stimuli whereas widthsremain constant at 40 microseconds.

In both polygraphs one notes the reproducible skin conductivity response(intermediate plot) in close temporal relationship, at about 500 mseclatency, with the frequency increase phase of the stimulation. In bothcases, the average conductance trend tends to fall. However, theabsolutely original element and result of the disclosed inventionconsists of the close reproducibility of the responses regardless of themanner that they assume compared with the three phases of stimulationfrequency.

This indicates that there is a direct dose-response relationship betweenthe variability of the frequency of the electric stimuli which have aconstant amplitude and are below the pain threshold andcatecholaminergic vegetative efferents, inasmuch as skin conductance isdirectly influenced by local sweating, which is in turn carried, in thepalm of the hand, by sympathetic innervation.

With regard to variation in skin conductance, some characteristics haveemerged that are practically constant and independent of the subjectsubjected to stimulation and are disclosed below.

Above all, during the phase of rapid increase in stimulation frequency,a complex twin, triple or quadruple negative deflection phase occursthat is constant in each test during the three increase phases in bothsubjects and is therefore independent of the subjects themselves.

Again, the average trend of conductance under stimulation appeared to beindifferently ascending or descending in the different polygraphs.Characteristic trends and morphologies of the polyphase response belongto each subject.

Lastly, the overall duration of the polyphase response during theincrease phase varies from 14 to 19 seconds; the greatest negativedeflection is always the last of the complex and always occurs followingthe cessation of the incremental phase of the stimulus, with latency ofapproximately 1.5 sec. The negative components of the complex, which arevariable between subjects and over the course of different measurements,always appear in relation to the first seconds of increase of thestimulation frequency.

In terms of the surface electromyogram, in both subjects and in all themeasurements made, the same phenomena were ascertained, as describedbelow.

During the preparatory stimulation, at a frequency of 1 Hz, there was nomuscle response; during the increase phase composite motor unitpotential was formed with increasingly shorter latency and increasinglyhigher amplitude until the formation of composite muscle actionpotential (cMAPSs) with minimum latency and maximum amplitude at thepeak of the stimulation frequency.

The minimum appearance latencies of the cMAPSs correspond to thelatencies that are detectable by means of electroneurography usingstandard methods. On the other hand, compared with the above-mentionedmethod of detection of the cMAPSs, the amplitudes are reduced by about30%.

Each cMAP follows on from each stimulus and the isoelectric line of theplot returns after the cMAP to the value 0.

The top plot simply describes the production of composite motorpotentials (cMAPs) in close temporal relation with the stimuli of thesequence. The inventive and original element consists of the fact thatthe first cMAPs appear only in the phase of increase of the frequency ofthe stimulation, according to a model that is absolutely analogous tothe temporal recruitment of stimuli of the same amplitude, but placed inan increasing sequence over time (in a completely analogous manner towhat occurs in the classical nerve-muscle physiological model).

The second phenomenon should also be pointed out, i.e. the one accordingto which, in addition to recruiting in frequency the number of cMAPs,the increase in stimulation determines the total amplitude of the cMAPS.This means that DCRT-type stimulation can perfectly emulate the actionof a nerve fibre that innerves a skeletal muscle.

A second experimental procedure is based on the use of a reactivationsequence of the microcirculation, or ATMC, whose frequency and widthcharacteristics are disclosed in the graph in FIG. 6.

This second procedure had the object of showing the validity of thehypothesis that an ATMC sequence, suitably designed to obtain thedesired effect, has a prevalent action on the motility of themicrocirculation, i.e. of the smooth sphincters of the arterioles andvenules of the subcutaneous layer.

In this case, and for this object, stimulation was carried out byrecording with a doppler flow laser-apparatus that is able to measurethe degree of perfusion of the microcirculation, i.e. of thesubcutaneous haematic flow, in addition to other correlated and synergicparameters, i.e.: O₂ saturation, CO₂ saturation and skin temperature.

To view the significant components of this sequence, with reference toFIGS. 5, 7, 8 and 9 the constitution of the ATMC sequence in threesubsequences known as S1, S2, S3 is discussed below.

S1 and S3 are both characterized by a frequency increase phase, withdistinct time modes, whilst S2 is mainly constituted for producingvariability in the width of the different stimuli, in a graduallyincreasing range of frequencies but in such a way as to reduce thebioreaction until it is stabilised.

More in detail, during the S1 subsequence, a sequence that typically hasa relaxing effect and which is very similar to the DCTR sequencedisclosed above, different subphases are carried out wherein, after afirst subphase with a 1-Hz frequency of mere adaptation, the frequencywith a constant amplitude is gradually increased, thereby also graduallydecreasing the bioreaction. Subsequently, the frequency is increasedmuch more rapidly up to the target of 19 Hz.

Subsequently, the subsequence S2 is carried out, which in turn issubdivided into four parts, S2-A, S2-B, S2-C and S2-D. In thissubsequence, after a phase wherein the amplitude is rapidly increased upto the instant 1 (S2-A), the frequency is made to gradually increase,and as a result the bioreaction rapidly falls to the instant 2 (S2-B).At this point the amplitude is reset, which will again increase at aconstant frequency up to instant 3 (S2-C); the frequency will thereafteronce again gradually increase at constant amplitude, as a result thebioreaction will also gradually fall to the instant 3 (S2-D).

In this way, the bioreaction is made to vary in a discontinuous manner,producing points of variation of the jump gradient, i.e. the points 1, 2and 3.

To conduct the experiments, the sensor of the laser apparatus was placedon the extensor surface of the wrist (non-smooth skin). The stimulationelectrodes were placed with the anode (stimulator) on the route of theradial nerve on the extensor surface of the third distal of the forearmand with the cathode placed near the proximal capitulum of the secondphalanx. Furthermore, measuring electrodes of skin conductivity werepositioned, in the same way as the first experimental proceduredescribed above used to vary the effects of the DCTR sequence. The ATMCsequence was administered also in this case to two healthy subjects.

On the first a polygraph was first recorded during electric stimulationwith an ATMC sequence and subsequently another polygraph of similarwidth was recorded but in absence of electric stimulation.

On the second subject two polygraphs were recorded, one of whichcompares responses during and after raising local skin temperature to44° C. This thermal shock was induced by the instrument itself, whoselaser probe in contact with the skin is provided with a thermistor ableto heat the face of the probe in contact with the skin until a desiredtemperature is reached.

In this context it is important to stress that that was done becauseskin thermal stimulation is reported in the literature to be the maximumstimulation to obtain vasodilatation. Therefore in this case theintention is also to carry out a comparison.

Any stimulation carried out is made up of three basic identicalsequences of the ATMC type.

The parameters that are most subject to variation are local flow,temperature and skin conductance, whereas oxygen and carbon-dioxidesaturation do not show suggestive variations in relation to the sequenceof the different stimulation phases. The analysis that is suggested bythe detailed evaluation of the recorded plots enables the apparentsynchronisation and desynchronisation of flow variation to be checked inrelation to the incremental phases of the stimulation sequences. Infact, during the first subphase consisting of 30 seconds of constantstimulation at 1 Hz and at 40 microseconds of pure preparation(considerable ineffective stimulation), there is an increase in theaverage oscillation frequency of the flow signal by means of dopplerlaser, which instead enters at lower frequencies in a temporalrelationship with the increase and decrease phases of the stimulationsequence.

In FIG. 10, the frequency spectra of the flow plot for each stimulationsubsequence have been analysed by a Fourier transform in the field offrequencies, and compared with the spectrum over a period of recordingwithout ATMC stimulation (base datum) and having a similar width (about50 sec).

It can be noted that during the period without stimulation theoscillation frequencies are rather dispersed and prevalent on the 1-2 Hzband, i.e. the typical frequency of the heartbeat, whilst during thethree stimulation subsequences frequencies are drastically synchronisedon the 0-1 Hz range.

In detail, the response mode of the flow in relation to specific momentsof the stimulation sequence is displayed. In the two subjects subjectedto polygraph, the most constant flow variations could be observed duringthe subsequence S2.

In the plot recorded for subject 1 during the subsequence S2 andillustrated in FIG. 11, the bottom line indicated the frequency trend ofstimulation, the top line indicated the virtually constant polyphasetrend of the local subcutaneous flow variation.

In the plot recorded for subject 2 during the subsequence S2 andillustrated in FIG. 12, the flow line has a ‘peaks’ pattern whereas theline of the stimulation frequencies has a ‘steps’ pattern.

Although apparently random, the flow oscillation phases coincideperfectly with the different frequency variation phases of the stimulus.

The close correlation between the trend of the subsequence S2 and theflow response can be displayed through individuation of flow peaks thatcoincide with the instants 1, 2, 3 disclosed previously.

With reference to FIG. 13, at the points of flow peak a reversal occursof the second derivative of the bioreaction and of the energytransferred to the tissue, and therefore of the determiningchronaxy/rheobasis correlated therewith, in view of the characteristicof the phenomenon of temporal summation that occurs, i.e. a drastic jumpvariation of the first derivative thereof.

In practice, the system produces a sequence of vasodilatations andvasoconstrictions with sequential increases and decreases of thehaematic flow of the microcirculation that produce a “pump” effect thatis evidently produced by neuromodulation of the neurovegetative and ofthe sympathetic system, which influences vasoactivity through the smoothmuscle of the smaller blood vessels (arterioles, capillary bloodvessels).

During the subsequence S2 of the ATMC sequence, characterized byalternating variations of the rheobasis, a vasoactive effect occurscomprising a succession of alternating phases of vasodilatation andvasoconstriction. This without doubt also produces a draining effect andabove all elasticisation of the microcirculation and its modulationaround a main carrying event that causes its average variation.

In a series of experiments conducted after those described above, thistype of vasoactive ATMC stimulation was associated with a vasodilativeor vasoconstrictive stimulus. If the ATMC stimulus is accompanied by avasodilative carrying stimulus, for example thermal heating stimulation,as in the case illustrated in FIG. 14, this association substantiallyenhances vasodilatation and the dose/response ratio.

On the other hand, if the ATMC stimulus is accompanied by avasoconstrictive carrying stimulus, such as for example thermal coolingstimulation, this association substantially enhances vasoconstriction.

In this case Lorenz™ stimulation by means of the ATMC sequence createseffective neuromodulation that is able to amplify the excitationphenomena of the primary and secondary neuroceptors. Consequently, it ispossible to use the ATMC vasoactive sequence also in combination withhyperthermia and cryotherapy treatments to enhance the effects of thelatter.

In this way localised neoplasms and solid tumours can be treated by thecombination of temperature effects with vasoactive effects.

If cryotherapy is combined with the vasoactive ATMC sequence thevasoconstrictive effects are increased, thereby producing localisedhypoxia in a tumour mass, with consequent necrosis of the latter.

Similarly, by combining the vasoactive ATMC sequence with a hyperthermictherapy important vasodilatation is obtained that amplifies thenecrotizing effect of the hyperthermia on a tumour mass.

In conclusion, it can certainly be stated that the Lorenz Therapy™stimulation sequences induce reproducible and constantneurophysiological responses; the ATMC and DCTR sequences are able tostimulate different functional contingents, including the striatedmuscle, the smooth muscle and the mixed peripheral nerve.

The stimulation sequences are assembled on three fundamental parameters:the width of the stimulus, the frequency of the stimulus and the timewherein different combinations of width/frequency follow. The generaloperating model reflects the digital-analogue transmission that occursin nervous transmission.

1-7. (canceled)
 8. The combination of: an electrostimulating apparatusfor applying electrical stimuli to biological tissues; and a device forexchanging heat with said biological tissues.
 9. The combinationaccording to claim 8, wherein said device for exchanging heat comprisesa device for heating said biological tissues.
 10. The combinationaccording to claim 8, wherein said device for exchanging heat comprisesa device for cooling said biological tissues.
 11. The combinationaccording to claim 9, wherein said device for exchanging heat comprisesa device for cooling said biological tissues.
 12. The combinationaccording to claim 8, wherein said device for exchanging heat comprisesa device for controlling the temperature of said biological tissues. 13.The combination according to claim 9, wherein said device for exchangingheat comprises a device for controlling the temperature of saidbiological tissues.
 14. The combination according to claim 10, whereinsaid device for exchanging heat comprises a device for controlling thetemperature of said biological tissues.
 15. The combination according toclaim 11, wherein said device for exchanging heat comprises a device forcontrolling the temperature of said biological tissues.
 16. Anelectrostimulating apparatus that generates a relaxing sequence suitablefor stimulating striated muscle fibre, based on three fundamentalparameters: the width of the electric stimulation, the frequency of saidstimulation and the intervals of time wherein a plurality ofwidth/frequency combinations follows.
 17. An electrostimulatingapparatus that generates a vasoactive sequence of activation of themicrocirculation suitable for stimulating the smooth muscle fibre andthe postsynaptic neuroceptors, based on three fundamental parameters:the width of the electric stimulation, the frequency of said stimulationand the time wherein a plurality of combinations of width/frequencyfollow.